Arsenic has been used as a therapeutic agent for more than 2,400 years. Until the 1930s, arsenic was used as a treatment for patients with chronic myelogenous leukemia. More recently, the use of arsenic in leukemia has resurfaced after reports from China that arsenic induced a high remission rate in acute promyelocytic leukemia (APL), including those who were resistant to therapy with all-trans retinoic acid.
The activity of arsenic (As2O3) in APL is in part related to the disappearance of the PML-RARα fusion protein, the gene product of the chromosomal translocation t(15,17) characteristic of APL, and the induction of differentiation. As23 can also induce apoptosis through a variety of mechanisms, which appear to be independent of PML-RARα degradation. In addition to causing mitochondrial toxicity, impairing microtubule polymerization, and deregulating a number of proteins and enzymes through binding to sulfhydryls groups, considerable evidence suggests that As2O3 induces the accumulation of reactive oxygen species (ROS) and subsequently, induces oxidative stress. Indeed, the intracellular redox status has been shown to be important in predicting whether a cell will respond to arsenic.
Recently it has been shown that As2O3 stimulates apoptosis in additional malignant cells including acute myeloid leukemia, chronic myeloid leukemia, myeloma and various solid tumor cells. However, higher concentrations of As2O3 are required to induce apoptosis in non-APL tumor cells, suggesting that higher, more toxic doses might be needed for clinical efficacy. Clinical trials are currently testing arsenic in the treatment of lymphoma and myeloma, but clear evidence of clinical benefit has, thus far, been largely restricted to patients with APL.
It would be highly desirable to increase the therapeutic index of arsenic.